Malaria remains among the most significant public health problems in the world. Since 40% of the world?s population living in malaria endemic areas, malaria is one of the most devastating parasitic diseases. More than 200 million infections and over 0.4 million of deaths were reported in 2015. Importantly, commonly used antimalarials lose potency at an alarming rate due to widespread prevalence of drug resistant parasites. For example, resistance to chloroquine, one of the most commonly used antimalarials, has been confirmed in nearly all regions affected by malaria. Artemisinin combination therapies (ACTs) have arisen to combat malaria resistant to traditional medicines, and presently serve as a last-resort treatment. Unfortunately, a recent WHO report indicates that resistance to artemisinin has emerged in more than five countries of South-East Asia. Due to the limited number of antimalarial chemotypes and rising P. falciparum resistance to most available medicines, new drugs are urgently required to combat this deadly disease. Herein, we propose the evaluation and optimization of two 4(1H)-quinolone chemotypes, namely the phenoxyethoxy-4(1H)-quinolones (PEQs) and the 1,2,3,4- tetrahydroacridin-9(10H)-ones (THAs), for their activity against the blood, liver, and transmission stages of the parasite. The PEQs and THAs are structurally related to 4(1H)-quinolone ELQ-300, whose advancement towards Phase I studies was deferred due to poor oral bioavailability, limiting preclinical safety and toxicity studies. Our preliminary data demonstrate that a variety of structural elements, which we identified, render the PEQs and THAs a better aqueous solubility than ELQ-300 without significantly reducing the antimalarial activity. Furthermore, the use of a solubilizing prodrug moiety has also shown to improve the 4(1H)-quinolone?s antimalarial activity in vivo. Based on this preliminary data, we hypothesize that increase of PEQ?s and THA?s aqueous solubility will improve the overall performance of 4(1H)-quinolone antimalarials and possibly provide entrance to preclinical development. Specifically, we propose to further optimize our PEQs and THAs as we identified specific substituents, which significantly increase aqueous solubility, while also maintain or improve antimalarial activity. Furthermore, we will also continue the optimization of a general prodrug approach. The proposed research has potential to provide orally bioavailable 4(1H)-quinolone-based malaria prophylactic regimens that (a) target blood, liver, and transmitting stages of the malaria parasites, (b) act against relapsing malaria including P. vivax, (c) encourage higher compliance in deployed service members, and (d) possibly optimize the application of existing malaria drugs reducing the impact of artemisinin resistant P. falciparum.